scholarly journals Salivary Aβ Secretion and Altered Oral Microbiome in Mouse Models of AD

2021 ◽  
Vol 17 (12) ◽  
pp. 1133-1144
Author(s):  
Angela M. Floden ◽  
Mona Sohrabi ◽  
Suba Nookala ◽  
Jay J. Cao ◽  
Colin K. Combs
Keyword(s):  
Matched Control ◽  
Amyloid Β ◽  
Cell Types ◽  
Oral Microbiome ◽  
Aβ Peptide ◽  
Prior Work ◽  
Wild Type ◽  
Male And Female ◽  
Amyloid Aβ ◽  
The Brain

Background: Beta amyloid (Aβ) peptide containing plaque aggregations in the brain are a hallmark of Alzheimer’s Disease (AD). However, Aβ is produced by cell types outside of the brain suggesting that the peptide may serve a broad physiologic purpose. Objective: Based upon our prior work documenting expression of amyloid β precursor protein (APP) in intestinal epithelium we hypothesized that salivary epithelium might also express APP and be a source of Aβ. Methods: To begin testing this idea, we compared human age-matched control and AD salivary glands to C57BL/6 wild type, AppNL-G-F , and APP/PS1 mice. Results: Both male and female AD, AppNL-G-F , and APP/PS1 glands demonstrated robust APP and Aβ immunoreactivity. Female AppNL-G-F mice had significantly higher levels of pilocarpine stimulated Aβ 1-42 compared to both wild type and APP/PS1 mice. No differences in male salivary Aβ levels were detected. No significant differences in total pilocarpine stimulated saliva volumes were observed in any group. Both male and female AppNL-G-F but not APP/PS1 mice demonstrated significant differences in oral microbiome phylum and genus abundance compared to wild type mice. Male, but not female, APP/PS1 and AppNL-G-F mice had significantly thinner molar enamel compared to their wild type counterparts. Conclusion: These data support the idea that oral microbiome changes exist during AD in addition to changes in salivary Aβ and oral health.

scholarly journals Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

2020 ◽  
Vol 14 ◽  
Author(s):  
Katiuscia Pagano ◽  
Simona Tomaselli ◽  
Henriette Molinari ◽  
Laura Ragona
Keyword(s):  
Molecular Weight ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Natural Compounds ◽  
Preventive Therapy ◽  
Small Subset ◽  
Aβ Peptide ◽  
Aβ Oligomers ◽  
Chemical Structures ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

scholarly journals Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mireia Tarrés-Gatius ◽  
Lluís Miquel-Rio ◽  
Leticia Campa ◽  
Francesc Artigas ◽  
Anna Castañé
Keyword(s):  
Motor Coordination ◽  
Sensory Information ◽  
Wild Type ◽  
Thalamic Nuclei ◽  
Treatment Resistant ◽  
Cortical Networks ◽  
Male And Female ◽  
Female Mice ◽  
Antidepressant Effects ◽  
The Brain

AbstractAcute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

Opiate-induced Analgesia Is Increased and Prolonged in Mice Lacking P-glycoprotein

2000 ◽  
Vol 92 (5) ◽  
pp. 1392-1399 ◽  
Author(s):  
Susan J. Thompson ◽  
Kari Koszdin ◽  
Christopher M. Bernards
Keyword(s):  
Knockout Mice ◽  
Transmembrane Protein ◽  
Analgesic Efficacy ◽  
Cell Types ◽  
Acute Administration ◽  
Morphine Analgesia ◽  
Wild Type ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors ◽  
The Brain

Background P-glycoprotein is a transmembrane protein expressed by multiple mammalian cell types, including the endothelial cells that comprise the blood-brain-barrier. P-glycoprotein functions to actively pump a diverse array of xenobiotics out of the cells in which it is expressed. The purpose of this study was to determine if P-glycoprotein alters the analgesic efficacy of clinically useful opioids. Methods Using a standard hot-plate method, the magnitude and duration of analgesia from morphine, morphine-6-glucuronide, methadone, meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice and in FVB mice lacking P-glycoprotein [mdr1a/b(-/-)]. Analgesia was expressed as the percent maximal possible effect (%MPE) over time, and these data were used to calculate the area under the analgesia versus time curves (AUC) for all opioids studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100 mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also determined. Results Morphine induced greater analgesia in knockout mice compared with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and morphine brain concentrations were greater in knockout mice. Analgesia was also greater in knockout mice treated with methadone and fentanyl but not meperidine or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine analgesia in wild-type mice but had no effect in knockout mice. Conclusions These results suggest that P-glycoprotein acts to limit the entry of some opiates into the brain and that acute administration of P-glycoprotein inhibitors can increase the sensitivity to these opiates.

scholarly journals The Spike Glycoprotein of Murine Coronavirus MHV-JHM Mediates Receptor-Independent Infection and Spread in the Central Nervous Systems of Ceacam1a−/− Mice

2007 ◽  
Vol 82 (2) ◽  
pp. 755-763 ◽  
Author(s):  
Tanya A. Miura ◽  
Emily A. Travanty ◽  
Lauren Oko ◽  
Helle Bielefeldt-Ohmann ◽  
Susan R. Weiss ◽  
...  
Keyword(s):  
Hepatitis Virus ◽  
Lethal Dose ◽  
Cell Types ◽  
Wild Type ◽  
Spike Glycoprotein ◽  
Susceptibility To Infection ◽  
Spread Of Infection ◽  
The Brain ◽  
Murine Coronavirus

ABSTRACT The MHV-JHM strain of the murine coronavirus mouse hepatitis virus is much more neurovirulent than the MHV-A59 strain, although both strains use murine CEACAM1a (mCEACAM1a) as the receptor to infect murine cells. We previously showed that Ceacam1a −/− mice are completely resistant to MHV-A59 infection (E. Hemmila et al., J. Virol. 78:10156-10165, 2004). In vitro, MHV-JHM, but not MHV-A59, can spread from infected murine cells to cells that lack mCEACAM1a, a phenomenon called receptor-independent spread. To determine whether MHV-JHM could infect and spread in the brain independent of mCEACAM1a, we inoculated Ceacam1a −/− mice. Although Ceacam1a −/− mice were completely resistant to i.c. inoculation with 106 PFU of recombinant wild-type MHV-A59 (RA59) virus, these mice were killed by recombinant MHV-JHM (RJHM) and a chimeric virus containing the spike of MHV-JHM in the MHV-A59 genome (SJHM/RA59). Immunohistochemistry showed that RJHM and SJHM/RA59 infected all neural cell types and induced severe microgliosis in both Ceacam1a −/− and wild-type mice. For RJHM, the 50% lethal dose (LD50) is <101.3 in wild-type mice and 103.1 in Ceacam1a −/− mice. For SJHM/RA59, the LD50 is <101.3 in wild-type mice and 103.6 in Ceacam1a −/− mice. This study shows that infection and spread of MHV-JHM in the brain are dependent upon the viral spike glycoprotein. RJHM can initiate infection in the brains of Ceacam1a −/− mice, but expression of mCEACAM1a increases susceptibility to infection. The spread of infection in the brain is mCEACAM1a independent. Thus, the ability of the MHV-JHM spike to mediate mCEACAM1a-independent spread in the brain is likely an important factor in the severe neurovirulence of MHV-JHM in wild-type mice.

scholarly journals Down-regulation of cyclin D2 in amyloid β toxicity, inflammation, and Alzheimer’s disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259740
Author(s):  
Grzegorz A. Czapski ◽  
Magdalena Cieślik ◽  
Emilia Białopiotrowicz ◽  
Walter J. Lukiw ◽  
Joanna B. Strosznajder
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Aβ Peptide ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Cyclin D2 ◽  
Aβ Peptides ◽  
Expression Of Genes ◽  
Genes Encoding

In the current study, we analyzed the effects of the systemic inflammatory response (SIR) and amyloid β (Aβ) peptide on the expression of genes encoding cyclins and cyclin-dependent kinase (Cdk) in: (i) PC12 cells overexpressing human beta amyloid precursor protein (βAPP), wild-type (APPwt-PC12), or carrying the Swedish mutantion (APPsw-PC12); (ii) the murine hippocampus during SIR; and (iii) Alzheimer’s disease (AD) brain. In APPwt-PC12 expression of cyclin D2 (cD2) was exclusively reduced, and in APPsw-PC12 cyclins cD2 and also cA1 were down-regulated, but cA2, cB1, cB2, and cE1 were up-regulated. In the SIR cD2, cB2, cE1 were found to be significantly down-regulated and cD3, Cdk5, and Cdk7 were significantly up-regulated. Cyclin cD2 was also found to be down-regulated in AD neocortex and hippocampus. Our novel data indicate that Aβ peptide and inflammation both significantly decreased the expression of cD2, suggesting that Aβ peptides may also contribute to downregulation of cD2 in AD brain.

scholarly journals Measurement of cerebral ABCC1 transport activity in wild-type and APP/PS1-21 mice with positron emission tomography

2019 ◽  
Vol 40 (5) ◽  
pp. 954-965 ◽  
Author(s):  
Viktoria Zoufal ◽  
Severin Mairinger ◽  
Markus Krohn ◽  
Thomas Wanek ◽  
Thomas Filip ◽  
...  
Keyword(s):  
Age Groups ◽  
Brain Regions ◽  
Emission Tomography ◽  
Protective Mechanism ◽  
Transport Activity ◽  
Wild Type ◽  
Positron Emission ◽  
Amyloid Aβ ◽  
Pet Scans ◽  
The Brain

Previous data suggest a possible link between multidrug resistance-associated protein 1 (ABCC1) and brain clearance of beta-amyloid (Aβ). We used PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) to measure cerebral ABCC1 transport activity in a beta-amyloidosis mouse model (APP/PS1-21) and in wild-type mice aged 50 and 170 days, without and with pretreatment with the ABCC1 inhibitor MK571. One hundred seventy days-old-animals additionally underwent [11C]PiB PET scans to measure Aβ load. While baseline [11C]BMP PET scans detected no differences in the elimination slope of radioactivity washout from the brain (kelim) between APP/PS1-21 and wild-type mice of both age groups, PET scans after MK571 pretreatment revealed significantly higher kelim values in APP/PS1-21 mice than in wild-type mice aged 170 days, suggesting increased ABCC1 activity. The observed increase in kelim occurred across all investigated brain regions and was independent of the presence of Aβ plaques measured with [11C]PiB. Western blot analysis revealed a trend towards increased whole brain ABCC1 levels in 170 days-old-APP/PS1-21 mice versus wild-type mice and a significant positive correlation between ABCC1 levels and kelim. Our data point to an upregulation of ABCC1 in APP/PS1-21 mice, which may be related to an induction of ABCC1 in astrocytes as a protective mechanism against oxidative stress.

scholarly journals Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alejandro Ruiz-Riquelme ◽  
Alison Mao ◽  
Marim M. Barghash ◽  
Heather H. C. Lau ◽  
Erica Stuart ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mouse Models ◽  
Potential Role ◽  
Amyloid Β ◽  
Distinct Pattern ◽  
Aβ Peptide ◽  
Relative Contribution ◽  
Unique Strain ◽  
The Brain

AbstractWhen injected into genetically modified mice, aggregates of the amyloid-β (Aβ) peptide from the brains of Alzheimer’s disease (AD) patients or transgenic AD mouse models seed cerebral Aβ deposition in a prion-like fashion. Within the brain, Aβ exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal Aβ variants to the seeding behavior of Aβ aggregates remains unknown. Here, we have investigated the relative seeding activities of Aβ aggregates composed exclusively of recombinant Aβ38, Aβ40, Aβ42, or Aβ43. Cerebral Aβ42 levels were not increased in AppNL−F knock-in mice injected with Aβ38 or Aβ40 aggregates and were only increased in a subset of mice injected with Aβ42 aggregates. In contrast, significant accumulation of Aβ42 was observed in the brains of all mice inoculated with Aβ43 aggregates, and the extent of Aβ42 induction was comparable to that in mice injected with brain-derived Aβ seeds. Mice inoculated with Aβ43 aggregates exhibited a distinct pattern of cerebral Aβ pathology compared to mice injected with brain-derived Aβ aggregates, suggesting that recombinant Aβ43 may polymerize into a unique strain. Our results indicate that aggregates containing longer Aβ C-terminal variants are more potent inducers of cerebral Aβ deposition and highlight the potential role of Aβ43 seeds as a crucial factor in the initial stages of Aβ pathology in AD.

scholarly journals Astrocytes respond to a neurotoxic Aβ fragment with state-dependent Ca2+ alteration and multiphasic transmitter release

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Cuong Pham ◽  
Karine Hérault ◽  
Martin Oheim ◽  
Steeve Maldera ◽  
Vincent Vialou ◽  
...  
Keyword(s):  
Glutamate Release ◽  
Amyloid Β ◽  
Mammalian Brain ◽  
Major Type ◽  
Aβ Peptide ◽  
Neuronal Function ◽  
Anion Channels ◽  
State Dependent ◽  
The Brain ◽  
Ad Mouse Model

AbstractExcessive amounts of amyloid β (Aβ) peptide have been suggested to dysregulate synaptic transmission in Alzheimer’s disease (AD). As a major type of glial cell in the mammalian brain, astrocytes regulate neuronal function and undergo activity alterations upon Aβ exposure. Yet the mechanistic steps underlying astrocytic responses to Aβ peptide remain to be elucidated. Here by fluorescence imaging of signaling pathways, we dissected astrocytic responses to Aβ25–35 peptide, a neurotoxic Aβ fragment present in AD patients. In native health astrocytes, Aβ25–35 evoked Ca2+ elevations via purinergic receptors, being also dependent on the opening of connexin (CX) hemichannels. Aβ25–35, however, induced a Ca2+ diminution in Aβ-preconditioned astrocytes as a result of the potentiation of the plasma membrane Ca2+ ATPase (PMCA). The PMCA and CX protein expression was observed with immunostaining in the brain tissue of hAPPJ20 AD mouse model. We also observed both Ca2+-independent and Ca2+-dependent glutamate release upon astrocytic Aβ exposure, with the former mediated by CX hemichannel and the latter by both anion channels and lysosome exocytosis. Our results suggest that Aβ peptide causes state-dependent responses in astrocytes, in association with a multiphasic release of signaling molecules. This study therefore helps to understand astrocyte engagement in AD-related amyloidopathy.

The Impact of the hAPP695SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways

2021 ◽  
pp. 1-19
Author(s):  
Mona Khorani ◽  
Gerd Bobe ◽  
Donald G. Matthews ◽  
Armando Alcazar Magana ◽  
Maya Caruso ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Redox Regulation ◽  
Amyloid Β ◽  
Tg2576 Mouse ◽  
Wild Type ◽  
Biochemical Pathways ◽  
Lower Fatty Acid ◽  
Hippocampal Tissue ◽  
The Impact ◽  
The Brain

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: Gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse.

scholarly journals Inflammation in Alzheimer’s disease: A friend or foe?

2018 ◽  
Vol 5 (8) ◽  
pp. 2552-2564 ◽  
Author(s):  
Samaila Musa Chiroma ◽  
Mohamad Taufik Hidayat Baharuldin ◽  
Che Norma Mat Taib ◽  
Zulkhairi Amom ◽  
Saravanan Jagadeesan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Beta Amyloid ◽  
Aβ Peptide ◽  
Cellular Mechanisms ◽  
Scientific Databases ◽  
Amyloid Aβ ◽  
The Brain ◽  
Convincing Data

Background: There is a dearth of precise information for molecular and cellular mechanisms responsible for the development of Alzheimer’s disease (AD). However, convincing data from clinical research and basic molecular biology have shown that inflammation of the brain is an integral part of AD. In this review, the role of inflammation in AD will be highlighted. Methods: Articles from credible scientific databases, such as ScienceDirect, Scopus, PubMed, Google Scholar and Mendeley, were searched and retrieved using keywords ‘inflammation’, ‘Alzheimer’s disease’, ‘tau’, and ‘beta amyloid’. Results: At present, there is no local inflammatory-inciting factor that is closely associated with AD, although it has been proposed that inflammation could be induced by pathologic hallmarks of AD, such as beta amyloid (Aβ) peptide plagues and neurofibrillary tangles (NFTs), or fragments of degenerated neurons. However, it is still unclear whether inflammation leads to the development of AD or if the pathological hallmarks of AD induce inflammation. Conclusion: Inflammation is, indeed, an integral part of AD. Further studies on inflammatory-targeted therapies for AD are highly recommended.

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